HUMAN GENETIC DISEASE AND DYNAMIC MUTATIONS

人类遗传性疾病具有多种多样的后果， 一种新发现的突变遗传性疾病，如脆性 X综合征是美国智力迟钝的主要原因，亨廷顿 肯尼迪病和强直性肌营养不良都是由 在基因中一个核苷酸三联体的不寻常的扩增， 疾病在正常个体的基因中， 存在三重峰。突变，有时被称为“前- “突变”，然后发生，增加道长度，但 无症状。随后，第二次突变发生， 较长的道长度，并与疾病状态有关。长期 研究的目的是了解这些扩张是如何发生的 最终的目标是能够影响这个过程， 症状前个体中这种扩张的可能性 所谓的前突变携带者提案的具体目标 是在真核生物模型中开发几个系统，贝克的 酵母（酿酒酵母）了解三联体的几个方面 重复疾病该提案的前两个目标是确定 这种扩增是否发生在酵母中， 观察显示。第三个目的是确定下列行为的后果： 当它被人工引入基因时， 编码酵母转录因子Adr 1 p。特别是要 确定突变是显性的还是隐性的，并研究其 对Adr 1蛋白结构和功能的影响。第四个目标 是确定这种扩张是否在遗传上是稳定的， 已被引入ADR 1基因。最终目标是发展一个 选择方案，这将使我们能够检测和研究的性质， 三重重复扩增，如果它们发生在酵母中。通过研究 在各种酵母突变株中三联体重复扩增的频率 我们希望确定它们是否是由DNA错误引起的， 复制或修复，如果是这样，以确定酶， 负责扩张。

Human genetic diseases having a diverse range of consequences are caused by a newly discovered type of mutation. Genetic diseases such as Fragile X Syndrome, the major cause of mental retardation in the US, Huntington disease, Kennedy disease, and myotonic dystrophy, are all caused by an unusual expansion of a nucleotide triplet in the gene responsible for the disease. In the gene of normal individuals short tracts of a repeated triplet are present. A mutation, sometimes referred to as a "pre- mutation", then occurs that increases the tract length but is asymptomatic. Subsequently, a second mutation occurs that leads to much longer tract length and is associated with the disease state. A long term objective of the research is to understand how these expansions took place with the eventual goal of being able to influence the process to decrease the likelihood of such an expansion in individuals who are presymptomatic carriers of the so-called pre-mutation. The specific aims of the proposal are to develop several systems in the model eukaryotic organism, Baker's yeast (Saccharomyces cerevisiae) to understand several aspects of triplet repeat diseases. The first two aims of the proposal are to determine whether such expansions occur in Saccharomyces as our preliminary observations suggest. The third aim is to determine the consequences of such an expansion when it has been artificially introduced into the gene encoding the yeast transcription factor Adr1p. In particular, we will determine whether the mutation is dominant or recessive, and study its effect on the structure and function of the Adr1 protein. The fourth aim is to determine whether such an expansion is genetically stable when it has been introduced into the ADR1 gene. The final aim is to develop a selection scheme that will allow us to detect and study the properties of triplet repeat amplifications if they occur in yeast. By studying the frequency of a triplet repeat expansion in various mutant strains of yeast we hope to determine whether they are caused by errors during DNA replication or repair, and if so, to determine the enzyme that is responsible for the expansion.